1. Field of the Invention
The present invention relates to therapies of amyloidosis. More particularly, the present invention relates to the use of 1-(2-fluorobiphenyl-4-yl)-alkyl carboxylic acid derivatives as agents capable of stabilizing the tetrameric native state of transthyretin for the prophylaxis and treatment of amyloidosis.
2. Discussion of the Background
Amyloidosis is a serious disease caused by extracellular deposition of insoluble abnormal fibrils. Systemic amyloidosis, with deposits in the viscera, blood vessels, and connective tissue, is usually fatal, causing about one per thousand deaths in developed countries.
Amyloid is deposited when there is: (i) sustained exposure to either normal or increased concentrations of a normal, potentially amyloidogenic, protein; (ii) when an abnormal amyloidogenic protein is produced as a consequence of an acquired disease; or (iii) when a gene mutation encodes an amyloidogenic variant protein. Fibrillogenesis results from reduced stability of the native fold of the fibril precursor protein, so that under physiological conditions it populates partly unfolded intermediate states which aggregate as stable amyloid fibrils.
Wild type-transthyretin (WT-TTR) is the normal plasma protein, synthesized by hepatocytes and by the choroid plexus, which transports thyroid hormone and retinol binding protein. TTR is inherently amyloidogenic and forms microscopic amyloid deposits of uncertain clinical significance in all individuals aged over 80 years. Massive deposits in the heart can also occur, causing fatal senile systemic amyloidosis (SSA). The inherent amyloidogenicity of wild type transthyretin is markedly enhanced by most of the reported >80 different point mutations which encode single residue substitutions in the transthyretin sequence. These mutations cause autosomal dominant adult onset hereditary amyloidosis, a universally fatal condition affecting about 10,000 patients worldwide. Said diseases are mainly grouped into two broad groups: familial amyloid polyneuropathy (FAP) and familial amyloid cardiomiopathy (FAC).
Amyloidogenic mutations occur in all ethnic groups, but by far the most common, V30M, clusters in three geographical foci: Northern Portugal, Northern Sweden, and parts of Japan. Other common amyloidogenic variants are T60A, L58H, L55P, I84S, and V112I. Among the pathogenic variants of TTR so far identified, the V 122I variant is of particular importance as is carried by 3-4% of African Americans: 1.3 million people, including 13,000 individuals homozygous for the mutation. It is the second most common pathogenic mutation in that population after sickle cell haemoglobin.
The variant V122I is particularly associated to cardiac transthyretin amyloidosis which presents as progressive, ultimately fatal, heart failure due to restrictive cardiomyopathy. Said pathology is rarely suspected and is usually misdiagnosed as coronary heart disease.
So far there is only a treatment available for FAP, i.e. gene therapy mediated by surgical replacement of the patient's liver, the organ secreting TTR subject to misfolding into the blood stream. The disadvantages of this approach include its invasiveness for the donor and recipient, the requirement for life-long immune suppression, and the limited effectiveness for some mutations for reasons that are not yet clear. Currently, there is no effective treatment either for SSA associated with WT-TTR deposition or for FAC. Therefore, a small molecule therapeutic strategy for all TTR-based amyloid diseases would be highly advantageous.
The most common approach to the potential treatment of transthyretin amyloidosis has been to identify small molecule ligands able to stabilize the native TTR tetrameric structure and thereby to prevent the dissociation of TTR into monomers which are in turn prone to misassembly leading to fibrillogenic aggregation. Ideally, good fibrillogenesis inhibitors should bind with high affinity, dissociate slowly, and exhibit high binding selectivity to TTR in the blood.
For example, several non-steroidal anti-inflammatory drugs (NSAIDS) such as diclofenac, flufenamic acid, diclofenac, flurbiprofen, and diflunisal have been shown to act as stabilizers of the tetrameric structure of TTR, inhibiting the formation of TTR amyloid fibrils in vitro. However, because said drugs are cyclooxygenase-2 inhibitors, their long-term administration could lead to gastrointestinal side effects.
Polyphenols such as trans-resveratrol are known to bind specifically to thyroxine binding sites of TTR (see Klabunde et al., Nat. Struct. Biol., 2000, 7, 312). However said kind of drugs are also known to be very aspecific, they might have low bioavailability, and may be endowed with several ancillary effects.
Further derivatives enabling for TTR binding are described in WO 2004/056315, WO 2006/086517, WO 2007022138, and WO 2009/040405.
In view of the above considerations, there is still the need for more effective products with an established safety profile in humans that binds to TTR and hence can be useful for treating TTR amyloidosis.
WO 2004/074232 and WO 2004/073705 disclose therapeutic agents for neurodegenerative diseases such as Alzheimer's disease.